Morphine-induced receptor endocytosis in a novel knockin mouse reduces tolerance and dependence

Kim, Joseph, Bartlett, Selena, He, Li, Nielsen, Carsten, Chang, Amy, Kharazia, Viktor, Ou, Chrissi, Waldhoer, Maria, Taylor, Stacy, Ferwerda, Madeline, Cado, Dragana, & Whistler, Jennifer (2008) Morphine-induced receptor endocytosis in a novel knockin mouse reduces tolerance and dependence. Current Biology, 18(2), pp. 129-135.

View at publisher (open access)



Opioid drugs, such as morphine, are among the most effective analgesics available. However, their utility for the treatment of chronic pain is limited by side effects including tolerance and dependence. Morphine acts primarily through the mu-opioid receptor (MOP-R) , which is also a target of endogenous opioids. However, unlike endogenous ligands, morphine fails to promote substantial receptor endocytosis both in vitro, and in vivo. Receptor endocytosis serves at least two important functions in signal transduction. First, desensitization and endocytosis act as an "off" switch by uncoupling receptors from G protein. Second, endocytosis functions as an "on" switch, resensitizing receptors by recycling them to the plasma membrane. Thus, both the off and on function of the MOP-R are altered in response to morphine compared to endogenous ligands. To examine whether the low degree of endocytosis induced by morphine contributes to tolerance and dependence, we generated a knockin mouse that expresses a mutant MOP-R that undergoes morphine-induced endocytosis. Morphine remains an excellent antinociceptive agent in these mice. Importantly, these mice display substantially reduced antinociceptive tolerance and physical dependence. These data suggest that opioid drugs with a pharmacological profile similar to morphine but the ability to promote endocytosis could provide analgesia while having a reduced liability for promoting tolerance and dependence

Impact and interest:

53 citations in Scopus
Search Google Scholar™
52 citations in Web of Science®

Citation counts are sourced monthly from Scopus and Web of Science® citation databases.

These databases contain citations from different subsets of available publications and different time periods and thus the citation count from each is usually different. Some works are not in either database and no count is displayed. Scopus includes citations from articles published in 1996 onwards, and Web of Science® generally from 1980 onwards.

Citations counts from the Google Scholar™ indexing service can be viewed at the linked Google Scholar™ search.

ID Code: 44984
Item Type: Journal Article
Refereed: Yes
Keywords: MOLNEURO
DOI: 10.1016/j.cub.2007.12.057
ISSN: 0960-9822
Subjects: Australian and New Zealand Standard Research Classification > BIOLOGICAL SCIENCES (060000) > BIOCHEMISTRY AND CELL BIOLOGY (060100)
Copyright Owner: Cell Press
Deposited On: 24 Aug 2011 22:16
Last Modified: 29 Feb 2012 14:35

Export: EndNote | Dublin Core | BibTeX

Repository Staff Only: item control page